Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene

The de novo occurrence of germline-activating thyrotropin receptor (TSHR) g ene mutations has been reported as the cause of sporadic nonautoimmune neon atal hyperthyroidism in eight children. We report the case of an Italian in fant girl who presented at birth with severe hyperthyroidism and goiter. Ul trasonografic examination of the infant's thyroid showed a diffuse goiter w ith a normal echogenic pattern. Serum antithyroglobulin, antithyroperoxidas e, and antithyrotropin receptor antibodies were undetectable. Treatment wit h propylthiouracyl, propranolol, and saturated potassium iodide solution st arted at 44 days of life with the resolution of thyrotoxic symptoms. Once e uthyroidism was achieved, the dose of propylthiouracyl was tapered, but hyp erthyroidism recurred. Auxological parameters showed an acceleration of lin ear growth and bone age. DNA was extracted from peripheral white blood cell s of the patient, the sister, and the two parents. All of exon 10 of the TS HR gene was amplified by polymerase chain reaction (PCR) and subjected to d irect sequencing. In the thyrotoxic infant girl, a substitution of cytosine to thymine was detected, changing isoleucine 568 into a threonine (I568T), located in the second extracellular loop. The normal sequence could also b e detected, indicating heterozygosis of the mutated allele. This mutation w as previously described as a somatic mutation in a patient with toxic thyro id adenoma. The sister and the parents of the propositus, all euthyroid, sh owed the wild-type TSHR gene. In conclusion, we describe a case of a de nov o germinal mutation of the TSHR causing severe congenital hyperthyroidism.